Quaternary salts of y-stilbazolines



Patented Oct. 13, 1953 UNITED STATES PATENT OFFICE 7 2,655,503 QUATERNARY SALTS or 'y-STILBAZOLINES Arthur P. Phillips, New York,and Juno 0 Gastillo, White Plains, N. Y Wellcome & 00. (U

., assignors to Burroughs A.) Inc., Tuckahoe,

N. Y., a corporation of l lew York No Drawing. Application March 29, 1951, Serial No. 218,279

4 Claims. (01. 260293) 1 The present invention relates to new quaternary salts of l-methyl 4-(4'-dimethylamino) stilbazolines having novel and unexpected curarelike properties. These compounds may be represented by the formula:

wherein R and R are lower alkyl radicals at 1 o I 2 tion of action is greatly prolonged. The compounds wherein both R and R are either ethyl, propyl or butyl show only vestigial curare-like The scheme of synthesis of these substances is as follows:

H: R EN: s )wmomQ-mom 2C Hal R R] HLN El CHICK: -N

(CH1). l 1' base base p-Dimethylaminobenzaldehyde is condensed with a y-picoline alkiodide to form a, 'y-stilbazole alkiodide. This, on catalytic reduction, takes up veniently prepared by treating the stilbazoline hydroiodide with R'I, thus quaternizing the less basic nitrogen atom, after which basification and addition of methyl iodide affords the final prodnot. One member of the last type can also be prepared by the main line of synthesis if pmethylethylaminobenzaldehyde be used in the initial condensation in place of p-dimethylaminobenzaldehyde.

This synthetic route up to the last step (i. e.,

through the stilbazoline hydroiodide) has already been described (Phillips, Jour. of 'Org. Chem., 12, 333 (1947); ibid. 14, 302 (1949); and Jour. Am. Chem. Soc., 72, 1850 (1950)), and the examples given here disclose only the process requiredto attain the diquaternary salts.

I As will be seen from the scheme of synthesis, X is normally I and, in the doses to be used therapeutically there is no obvious advantage in employing a difierent anion. However, it is easy by conventional methods to transform the iodides into chlorides, nitrates etc. Use of alkyl bromides inthe quaternization step affords bromides and use of dimethyl or diethyl sulfate gives metho and etho-sulfates. All non-toxic anions are to be regarded as equivalents for the purpose of this invention since the anion itself becomes infinitely diluted after injection by the enormous amounts of anions (especially chloride and phosphate anions) present in the body 'fluids. Only the cationic portion is of any importance for physiological purposes.

EXAMPLE 1 1-methyl-4-(4-dimethylaminophenethyl) piperidine bis methiodide The base obtained from 1 .5 g. (0.033 mole) of 1-methyl-4- (4 -dimethyl-aminophenethyl) piperidine hydroiodide (1-methyl-4-dimethylaminostilbazoline hydroiodide) (Phillips, J. Amer. Chem. Soc., 72, 1850 (1950)) was taken up in ether, and dried over potassium carbonate. The solution wasflltered from thedesiccant and evaporated. The residual base (8.3 g.) was dissolved in methanol, '8 cc. of methyl iodide was added, and the solution was refluxed 8 hours on a steambath. The solvent and excess methyl iodide were then evaporated and the diquaternary salt was crystallized from methanol-ethylacetate mixtures, M. P. HEB-185 Conversion to the by shaking with silver chloride in aqueous solution.

EXAM LE 2 1-ethyl-4-(4-dimethylaminophenethyl) piperidine b s methiodide chloride was accomplished residue was washed several times ether-insoluble residue was stirred with 10 cc. of

Similar treatment 01'. 'y-picoline n-propiodlde and n-butiodide afforded by the same synthetic route the l-n-propyl and l-n-butyl homologues.

EXAMPLE 3 1 methyl 4 (4-methylethylaminophenethul) piperidine bis 'methiodide Theihydroiodide of 1-methyl-4-(4'-dimethylaminophenethyl) piperidine (3.7 g.=0.01 mole) wasrefluxed' i hours with 5 cc. of ethyl iodide.

iodide was evaporated and the with ether. The

The excess ethyl r The solid was then dissolved in 10 cc. of methanol,

5 cc. of methyl iodide was added and the mixture was refluxed 3 hours. The product was recrystallized from methanol-ethyl acetate mixtures and then melted at 186.

AmlL-Calcd. for CwHznNzIz: C, 41.9; I, 46.7%. Found: C, 42.2; H, 6.1; I, 46.6%.

Similar procedures employing n-propyl iodide and n-butyl iodide in place of ethyl iodide result in the 4'-n-propyl and n-butyl homologues.

We claim:

1. A substance of the formula:

12 R /N S CHaCH: -N(CH|): 2X CH: wherein R and R. are lower alkyl radicals or which at least one is methyl, X" is the anion of a non-toxic acid and S indicates saturation of the ring.

2. A salt of the divalent cation:

011051 s femoraQfiwam in combination with a non-toxic acid.

3. A salt of the divalent cation:

in combination with a non-toxic acid. 4. A salt 01 the divalent cation:

in combination with a non-toxic acid.

ARTHUR P. PHILLIPS. JULIO C. CASTILLO.

References Cited in the file of this patent 

1. A SUBSTANCE OF THE FORMULA: 